In view of the high mortality of diabetics suffering from microangiopathies there is an urgent need to clarify the underlying pathogenetic mechanisms as well as to formulate a sensitive and specific diagnostic protocol. We propose therefore to undertake a systematic examination of the pathogenesis of cutaneous diabetic microangiopathy. Specifically, the following hypotheses will be tested: (1) It has been suggested that diabetic cutaneous microangiopathies are pathogenetically related to decreased nervous vasomotor control of the cutaneous microvasculature. Furthermore, because under normal conditions the non-nutritional vascular channels appear to be under greater nervous control than the nutritional channels, we assume that an impairment of nervous control will have a more profound effect on the non-nutritional communications. (2) Extrapolating the relative frequent occurrence of reduced sudomotor activity in the lower extremity of diabetics, we postulate a more frequent impairment of the cutaneous nervous control in the lower than in the upper extremities of these patients. (3) Although an overall decrease in O2 availability (related to changes in hemoglobin affinity or red blood cell properties) has been reported, its relevance however, as a cause of tissue hypoxia has not been established. In order to provide reliable evidence that reduced perfusion of the cutaneous microvasculature is indeed of microvascular origin, the following approaches are proposed. a) In the first place, the presence or absence of large artery occlusive disease will be established in every examined patient by using a set of standard noninvasive tests. b) The state of nervous control of the cutaneous circulation will be examined by indirect cold sensitivity and inspiratory gasp response (skin perfusion monitored by laser Doppler fluxmetering (LDF) and will be correlated with electrophysiologically documented peripheral neuropathy. c) The nutritional as opposed to non-nutritional flow components will be determined by the combined application of venous occlusion plethysmography (total blood flow) and epicutaneous 133 Xenon wash-out (nutritional flow). d) Finally, changes in tissue oxygen availability will be examined by the transcutaneously monitored pO2 post-occlusion reactive hyperemia (PORH) response normalized by the LDF-PORH response. The clarification of the pathogenesis of cutaneous diabetic microangiopathy will lead to its better understanding and an earlier diagnosis and thus to a reversal of an otherwise progressing underlying disease.